Introduction

Colorectal cancer in the younger age group is rare with an incidence of 1.3 – 2 cases per million population.[1] Most cases occur in the 2nd decade of life.[2] This type of cancer accounts for 5-15% of total colorectal cancer cases and is thought to be clinically aggressive.[3] The prognosis of young patients presenting with colorectal cancer is generally poor.

The poor prognosis is thought to be due to predominance of mucinous histopathology, lack of a high index of suspicion in this age group with most cases being treated for amoebiasis, granulomatous infections, worm infestations resulting in delay in diagnosis and treatment with most cases presenting at an advanced stage.

In this retrospective study, we have reviewed the clinical presentation, behavior and response to treatment in cases of colorectal cancer in young Indian patients (those below 25 years of age) and have attempted to assess if there are any significant differences with respect to the data available in existing literature.

Methods

A total of 32 patients of colorectal carcinoma aged between 10 to 25 years, registered in our department from 1st January 2000 to 31st December 2006, were selected for this study. All patients had preoperative computed tomography (CT) scans done to map the extent of disease. Diagnoses were made on the basis of histopathological examination.

A retrospective analysis was done on the patient profile, mode of presentation, disease load and their response to treatment. Patient survival at two years was also evaluated on the basis of number of cases remaining free of disease at one and two years post treatment; as well as number of survivors irrespective of disease load at one and two years post treatment. This was compared with existing literature and conclusions have been attempted to ascertain whether there are any differences in the presentation and behavior of Indian colorectal cancer patients as seen in our institution.

Results

Patient characteristics are enlisted in Table 1. In this retrospective study, over a period of 6 years, we reviewed 32 cases of colorectal cancers in individuals aged 10 to 25 years. In this same period, the total number of colorectal carcinomas registered at our centre was 324. Thus the incidence of cases between 10-25 years of age was 9.9% of the total number of colorectal cancer patients registered at our institute, which correlates well with reported literature. The mean age of presentation in our study was 20.4 years which correlates well with reported western literature that colorectal cancer in the young is mostly seen in the second decade of life. The median age at presentation was 21.5 years. About 50% of our patients presented in the age group of 21–25 years (young adults), while another 30% cases were in the adolescent age group (15- 20 years) and about 20% in the pediatric age group with youngest case presenting at 10 years of age. Nineteen percent of cases were below the age of 15 years. Twenty five cases (78%) presented with duration of disease less than or equal to one year, while only 7 cases (22%) presented with symptoms of more than one year duration. The average duration of presenting complaints was 11.7 months; correlating well with established literature that this type of colorectal cancer has a short history. The male to female distribution was almost equal, with a slightly higher female predominance.

More than two-thirds of the cases presented with locally advanced disease and this when combined with metastatic disease amounted to more than four-fifths of the cases (81%; stage III – 69%, stage IV – 12%). There were no stage I cases in our study population. Nodal involvement was seen in 12 (38%) cases and metastatic disease in another 4 (12%) cases. Of these, fifteen percent cases had more than seven nodes positive for tumor deposits; while perinodal extension was seen in another 4 (13%) cases. Another 14 (44%) cases had unknown nodal status of which 10 (31%) cases had stage III disease. That is another 10 (31%) cases had a high probability of nodal involvement; amounting to more than two-thirds of cases with known or probable nodal involvement; correlating well with reported literature of the high rate of disease presenting in advanced stage.

There was no associated family history or past history of inflammatory bowel disease in any case. Around two-thirds of cases (24 out of 32) did have history of worm infestation or had taken anti-helminthic treatment; but this was not related in time to disease presentation. No specific dietary factors could be elicited; around 60% of cases (19 out of 32) had nonvegetarian dietary habit. Around 70% of cases studied (22 out of 32) were from the area of western Uttar Pradesh and northern Madhya Pradesh. There was no significant history of sexual contact elicited from the studied cases.

The rectum was the most commonly involved site, seen in 81% cases, followed by the sigmoid colon (19% cases) and then the descending colon. Anal canal was also involved in 12% cases. The sites of metastases were peritoneum, retroperitoneal lymph nodes and prostate. However of the four cases having metastatic disease, peritoneum was involved in two cases, prostatic involvement was noted in one case and retroperitoneal nodes were involved in one case. A majority of the patients presented with pain, altered bowel habits and bleeding per rectum (Table 1). The most common derangement in bowel habit was an increased frequency of passing stools.

Patients presenting with obstruction had the worst response with most of the cases presenting with perforation (8 out of 10 cases) and tumor spillage; and 9 out of 10 cases with obstruction had either progressive disease (2 cases) or were unable to continue their treatment (7 cases). All the four cases presenting with ascites also had obstruction and none of these cases showed response to treatment; 2 of the cases could not complete treatment.

On histopathological review (Table 2) we noticed that the most common type of malignancy was the mucinous or mucin secreting adenocarcinoma, accounting for 31% of cases. Alongwith signet cell carcinoma; both together accounted for half (50%) the total number of cases (Table 2). This correlates well with western literature. Half the patients (50%) had grade 3 tumor, while grade 2 tumors accounted for 22% and grade 1 tumors were noted in 16%. Twelve percent cases had grade 4 disease. Thus higher grade (3 & 4) tumors accounted for 62% of the cases. Poorly differentiated carcinomas totaled 4 cases (3 cases poorly differentiated adenocarcinoma and 1 case of squamous cell carcinoma). Moderately differentiated adenocarcinoma was seen in only 19% cases, in contrast to older age group, where moderately differentiated tumours make up most of the cases and mucinous type accounts for only about 15%of cases. Also perirectal spread and serosal involvement was seen in 75% and 84% of cases respectively, indicating advanced disease presentation in a majority of cases, again correlating well with reported western literature. The absence of liver metastases and the increased frequency of perirectal and peritoneal involvement in these cases of rectalcancer with predominance of mucinous – signet cell variety also correlates well with reported western literature.

Sixteen cases underwent surgery, of which radical surgery was performed in 13 cases and palliative colostomies in 4 cases (Table 3). In all cases of palliative surgery, the outcome was very poor with none of the patients responding or completing treatment. Radical surgery performed included radical colectomies (sigmoid, hemicolectomy) in 4 cases; abdominoperineal resection (APR) in 4 cases and low anterior resection (LAR) in 5 cases. Radiotherapy was used in 16 patients (Table 3); in 1 case with a palliative intent, in the rest radiotherapy was used either pre-operatively (3 cases), post-operatively (10 cases) or as radical treatment (2 cases). Dose given preoperatively was 40 Gy in 20 fractions followed by surgery after 4 weeks. Post operative radiation dose was 45-50 Gy in 5 weeks followed by maintenance chemotherapy. Concurrent chemotherapy given involved weekly 5-FU. Radical dose of radiotherapy given was 56-60 Gy in 6 weeks. Chemotherapy was used in 19 cases (Table 3); as neoadjuvant in 5 cases, adjuvant in 9 cases, concurrently with radiotherapy in 1 case and as palliative in 4 cases. On an average, 2.4 cycles of neoadjuvant chemotherapy was used in 5 patients, while an average of 3.4 cycles of adjuvant chemotherapy were given in 9 patients. Leucovorin – 5 FU was the most commonly used regime.

Response evaluation of the patients was done at completion of treatment (Figure 1), and further evaluation was undertaken at one and two years after completion of their treatment (Figure 2). WHO criteria were used for evaluation of response. Of the cases undergoing radical surgery, 3 cases had complete remission after 1 year of completion of treatment and 1 case had partial remission, an overall response rate of 31% was thus noted. Complete remission at 1 year after radiotherapy was seen in 2 cases who received post operative radiotherapy and in one case which received pre-operative radiation therapy. Twenty eight percent patients responded to therapy (CR in 12%, PR in 16%); at completion of 1 year post treatment, remission was maintained in only 12% cases (CR in 9% and PR in 3%) and only the same was noted in only 6% at 2 years. Disease free survival at one year was seen in 9% of cases and at two years in 6% of cases. Thus patients who responded only partially could not maintain the response, with four fifths of the partial responders relapsing within a year of completion of treatment. On the other hand, 75% of the complete responders were able to maintain remission (3 out of 4 cases) at one year of completion of treatment, while at 2 years post treatment, 50% (2 out of 4 cases) of the complete responders maintained disease free status. However, in our study, a large number of cases (31%) could not complete treatment or dropped out during follow up at evaluation because of an advancedstage at presentation; this number increased to 41% at one year of completion of treatment and 51% at two years. Twenty two percent of cases did not take any treatment.

Discussion

Colorectal cancer in the younger age group is a rare subtype, accounting for 5-15% of total colorectal cancer cases.[3] Incidence is 1.3 – 2 cases per million1 mostly occurring in the 2nd decade of life.[2] In the United States, the incidence of colorectal cancer is estimated at 2 cases per million; and it is the second most common GI malignancy in children and adolescents after liver tumors.1,2 Patients younger than 36 years of age make only 1-2% of the total number of cases of colorectal carcinoma in most western populations.[4] However according to the Hong Kong Cancer Registry (Annual report 1995); patients younger than 36 years of age account for 3-5% cases in the east Asian population. Very few large scale studies have been undertaken in Indian patients and no studies have been performed to evaluate the genetic profile or study mutations in such patients.

Colorectal cancer in young patients has often been associated with underlying predisposing conditions like inflammatory bowel disease or hereditary polyposis syndromes.[5] These patients may also be at an increased risk of developing a second GI or extra-intestinal malignancies.[6] Gafanovich et al studied paediatric colorectal cancer patients who developed second malignancies, and reported a high frequency of micro-satellite instability and germline mismatch mutations in these tumours.[7] Another study from Hong Kong by Chan et al[8] showed that 84% of patients below 31 years of age carried a germline mutation in one of the mismatch repair genes. Bhatia et al[9] studied subjects with colorectal cancer diagnosed below 21 years of age. This study showed a six fold increase in the number of cases among relatives of patients diagnosed with colorectal cancer before 15 years of age.

This type of cancer is thought to be clinically aggressive. The prognosis of younger age patients presenting with colorectal cancer is generally poor and can be accounted for by a predominance of mucinous histopathology, lack of a high index of suspicion in cases presenting with rectal bleeding, constipation, vague pain abdomen or vomiting.[2,3,10] Lin et al[11] reported a higher incidence of Duke’s D (66%) lesions in the patients with subsequent very poor five year survival rates (0%) even after aggressive treatment. Most cases are treated for amoebiasis, granulomatous infections, and worminfestations, resulting in delayed diagnosis and treatment with most cases presenting at an advanced stage. A high level of suspicion followed by a digital rectal examination and a sigmoidoscopy and / or colonoscopy, if required, can help in diagnosing cases at an early stage.

The most common histologic types associated with childhood and younger age group colorectal cancers are the poorly differentiated varieties like the mucinous type or signet ring cell type seen in a majority of cases,[3,10,12,13] compared to around 5% of similar cases in older age groups.[13] The signet ring tumor has a higher propensity for early bowel wall invasion and involvement of peritoneal surface, with a much lesser propensity for metastases to the liver, behaving like ovarian tumors.[14] In our study also the most common histologic type was the mucinous type (34% patients); while the combined mucinous and signet ring types accounted for almost 50% of cases.

It has been noted that up to 80% of patients present with nodal or distant metastases, with the majority of tumors being inoperable.[13,15] The common sites of metastases include the omentum, peritoneum, liver, ovaries, lungs, brain and skeletal system.[10,11,14] In our study also, most cases though locally advanced, showed known nodal involvement in about 40% cases and metastatic disease in only 10% cases with another 31% cases having unknown nodal status with advanced disease.

The Indian scenario shows very sparse literature on this subject. Two studies, one by Rao et al[2] and another by Bhatia et al[16] show a predominance of mucinous type histopathology. This correlates well with the western literature. The mucinous type of tumor is deemed an aggressive type and is associated with a poorer prognosis. Bhatia et al[16] reviewed 7 cases over a 15 year period in western India. This study showed a predominance of left sided lesions in contrast to western literature which presents an even distribution. Six out of seven patients presented with locally advanced disease and could undergo only suboptimal resection. The median survival ranged from 2 – 13 weeks.

Unlike in the older age group, where the most common site of involvement is the lower rectum and also sigmoid colon; colorectal cancer in the younger age group according to western literature is evenly distributed in all parts of the large bowel. In a large series of 1025 patients, Dozois and Boardman17 reported that the left colon was the most common site of involvement as noted in 51% cases followed by rectum (49%); with 66% cases presenting in stages III and IV. In the series of 20 patients by Karnak et al[14] the authors reported that the rectosigmoid area was the most common site involved and mucinous type was most common histopathology. In our series also, the rectum was the most commonly involved site (80% patients) followed by the sigmoid colon (20% patients); correlating with the study by Bhatia et al[16] which showed predominant left sided disease.

This is in contrast to published western literature. The treatment of choice is curative surgical resection with wide margins with treatment guidelines remaining the same as for older age groups.[18] But this is rarely feasible because of the advanced stage at presentation and poor general condition. Pre-operative radiotherapy, chemo-radiation or the use of chemotherapy (Leucovorin / 5-FU) may be considered to increase resectability rates. Pratt et al in a phase II study showed favorable response in young patients with colorectal cancer.[19]

Guidelines for radiation and chemotherapy are same as in the older age group. However, usually the poor presenting general condition of patients precludes the use of radical treatment modalities; thus translating into very poor median and overall survival rates, especially in the Indian scenario. In our study also, a large percentage of patients could not complete treatment (31%) at immediate evaluation; even on follow after 1 year, 41% patients initially reviewed could not be evaluated.

To summarize, colorectal cancer in the younger age group and especially in children is a rare disease, occurring predominantly in the second decade of life with a median age of presentation in our study being 21.5 years. A high level of suspicion is necessary to diagnose this disease at an early and curable stage. In the younger age group, colorectal cancers differ from the older age group patients in presenting at a more advanced stage; mucinous type being more common with increased propensity for perirectal and peritoneal involvement, and far lesser incidence of liver metastases unlike in older patients; equivocal male / female distribution of cases and an equivocal distribution at all sites in large bowel unlike left sided predominant involvement in older patients. However in this aspect published Indian literature as well as this present study differ from western literature as left sided involvement is more common in young Indian patients.

Rectal bleeding in the younger age group should not be ignored or excluded only on the basis of the patient’s age and should be evaluated further with at least a digital rectal examination and sigmoidoscopy. Cases of bowel disorders in young patients should receive the same vigorous diagnostic evaluation and appropriate treatment as given to older age group cases with contrast studies, ultrasonography, computedtomography and endoscopy being essential procedures for both confirming the diagnosis and detecting the extent of disease. Completion of combined modality treatment with use of surgery, radiation as well as use of newer regimes like FOLFOX / CAPOX may yield higher response and survival rates. Failure to do so results in late presentation of cases at advanced stages with consequent dismal survival rates.

References